Endogenous cannabinoids acting at CB1 receptors (CB1) stimulate appetite, and CB1 antagonists show promise in the treatment of obesity. CB1 knockout (CB1-/-) mice are resistant to diet-induced obesity even though their caloric intake is similar to wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. In a recently completed study currently under review for publication, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB1 in mice increases the hepatic gene expression of the lipogenic transcription factor sterol response element-binding protein-1c (SREBP1c) and its targets acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FAS). Treatment with a CB1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, as measured by the incorporation of radiolabeled water into fatty acids. This finding suggests that hepatocytes express functional CB1. Indeed, using immunohistochemistry and Western blotting, we were able to demonstrate for the first time the expression of CB1 protein in the liver. In other experiments we found that feeding mice a high fat diet increases hepatic anandamide levels and basal rates of fatty acid synthesis, and the latter is reduced by CB1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP1c and FAS expression are similarly affected by CB1 ligands. These findings indicate that anandamide acting at hepatic CB1 contributes to diet-induced obesity, and the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation. We have previously reported that ethanol preference and voluntary intake are reduced in CB1-/- mice compared to their wild-type C57Bl6 littermates, in which the CB1 antagonist rimonabant reduces ethanol intake to levels seen in CB1-/- mice. These findings indicated that CB1 is involved in the regulation of voluntary ethanol consumption (Wang et al., PNAS 100:1393-98, 2003). If a similar mechanism is operative in humans, rimonabant may be used for the treatment of alcoholics. To test this, we have designed and started a phaseI/II clinical trial in collaboration with Drs. George, Herion and O'Malley and scientists from the Sanofi/Aventis company to test the safety and effectiveness of once daily rimonabant to reduce the desire to drink in young, heavy drinking individuals. The study, approved by the institional IRB, will include 40 subjects on a double-blind, placebo controlled basis. Subjects take 20 mg rimonabant daily for two weeks, following which they participate in a test where they have the option to drink 8 glasses of liquor over a 4 hour period, followed by a neuropsychiatric assessment for their subjective desire and response to drinking as well as a neuroendocrine evaluation. The study is currently in progress. If found effective, rimonabant may become only the third drug to be used for the treatment of alcoholics in the United States (after naltrexone and acamprosate). We have further explored the role of the endocannabinoid system in alcohol drinking behavior using C57BL6 mice deficient in fatty acid amidohydrolase, the enzyme responsible for the selective degradation of the endocannabinoid anandamide. The preliminary results indicate that in a two bottle/free choice paradigm where mice can drink either water or a 20% alcohol solution, FAAH-/- mice have significantly higher prepference for the alcohol solution than their wild-type littermates, and display a significantly greater alcohol deprivation effect (ADE), i.e. a temporary increase in alcohol intake when access to alcohol is suspended for a two week period and is then reinstated. These experiments, which suggests that anandamide is the endocannabinoid involved in regulating ethanol preference, are in progress.